Soluble Receptors for Advanced Glycation End-Products and PCI

Overview

It is hypothesized that patients with low pre-PCI serum levels of sRAGE should receive DES implantation and/ or procedures taken to increase serum levels of sRAGE and/ or decrease the serum levels of AGE. The purpose of this pilot study is to afford invasive cardiologists with additional evidenced based information to guide their decision as to which patients should receive a BMS or DES for coronary implantation. The objectives of the study are to determine whether or not: 1. Patients with low pre-PCI serum levels of sRAGE who receive bare metal stents develop restenosis 2. Patients with high pre-PCI serum levels of sRAGE who receive bare metal stents will have reduced risk of the development of restenosis 3. Patients with low pre-PCI serum levels of sRAGE who receive drug eluting stents will have an increased risk of the development of restenosis

Advanced glycation end products (AGE) are irreversible adducts formed from the non-enzymatic glycation and oxidation of proteins, lipids and nucleic acids. 1-4 AGE interacts with three types of cell receptors for advanced glycation end products (RAGE) namely full-length RAGE, N-truncated and C-truncated soluble receptors for AGE (sRAGE). The interaction of full-length RAGE with AGE increases the expression of adhesion molecules, including soluble vascular cell adhesion molecule-1 (sVCAM-1) and the cytokine tumor necrosis factor-α (TNF- α) activation of nuclear factor kappa B (NFκB) which in turn increases the expression of proinflammatory genes for adhesion molecules and cytokines, and the generation of reactive oxygen species (ROS). The function of N-truncated RAGE is poorly understood. sRAGE is not membrane bound and circulates in the plasma. Acting as a decoy for RAGE ligands (AGE), sRAGE competes with full-length RAGE for ligand binding. Consequently, sRAGE plays a protective role by preventing activation of full-length RAGE. Adhesion molecules, cytokines, and ROS are involved in the development and progression of atherosclerosis and lesion instability. The AGE and RAGE axis is involved in the development atherosclerosis in diabetes. Balloon injury in carotid artery and endothelial denudation in animal models increases the levels of RAGE and AGE in the arterial wall and produce neointimal hyperplasia. Treatment with sRAGE in animal models reduces neointimal growth, decreases smooth muscle cell proliferation and migration, and expression of extracellular matrix. sRAGE reduces the atherosclerotic lesions in Apo-E -/- mice and this effect is associated with a decrease in aortic VCAM-1 and tissue factor. Recently, we have demonstrated that the levels of serum sRAGE are lower while the serum levels of AGE, sVCAM-1 and TNF-α are higher in subjects with NSTEMI as compared to healthy controls 31. Furthermore, we have shown that the NSTEMI patients, who underwent PCI with BMS implantation and developed post-PCI restenosis after six-months, had lower serum levels of sRAGE as compared to those who did not 30. In the proposed study we expect to find that all patients with very low levels of serum sRAGE receiving either a BMS develop post-PCI restenosis while patients with very low serum levels of sRAGE receiving DES will increased rate of post-PCI restenosis. In addition, those patients with high levels of sRAGE who receive either BMS or DES will have a reduced rate of restenosis. This study has clinical significance because in our previous study (McNair et al, 2010), we demonstrated that low serum levels of sRAGE are associated with 100% restenosis following BMS implantation. In these situations DES implantation will be highly beneficial.